Pharmaceutical composition

ABSTRACT

A pharmaceutical composition is described. The composition may include: (i) a drug component including at least one pharmaceutically acceptable salt of glycopyrrolate; and (ii) a propellant component including 1,1-difluoroethane (HFA-152a).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/334,158, filed Mar. 18, 2019, which is the U.S. National Phase under35 U.S.C. § 371 of International Application No. PCT/GB2017/052761,filed Sep. 18, 2017, designating the United States and published inEnglish on Mar. 22, 2018, as WO 2018/051130, which claims priority toUnited Kingdom Application No. 1615917.0, filed Sep. 19, 2016 and toUnited Kingdom Application No. 1620519.7, filed Dec. 2, 2016, each ofwhich is incorporated by reference in its entirety.

FIELD

The present invention relates to the delivery of drug formulations froma medical device, such as a metered dose inhaler (MDI), using apropellant comprising 1,1-difluoroethane (HFA-152a). More particularly,the present invention relates to pharmaceutical compositions comprisingHFA-152a propellant and a drug formulation which is dissolved orsuspended in the propellant and to medical devices containing thosecompositions. The pharmaceutical compositions of the invention areparticularly suited for delivery from a pressurised aerosol containerusing a metered dose inhaler (MDI).

BACKGROUND

MDIs are the most significant type of inhalation drug delivery systemand are well known to those skilled in the art. They are designed todeliver, on demand, a discrete and accurate amount of a drug to therespiratory tract of a patient using a liquefied propellant in which thedrug is dissolved, suspended or dispersed. The design and operation ofMDIs is described in many standard textbooks and in the patentliterature. They all comprise a pressurised container that holds thedrug formulation, a nozzle and a valve assembly that is capable ofdispensing a controlled quantity of the drug through the nozzle when itis activated. The nozzle and valve assembly are typically located in ahousing that is equipped with a mouth piece. The drug formulation willcomprise a propellant, in which the drug is dissolved, suspended ordispersed, and may contain other materials such as polar excipients,surfactants and preservatives.

In order for a propellant to function satisfactorily in MDIs, it needsto have a number of properties. These include an appropriate boilingpoint and vapour pressure so that it can be liquefied in a closedcontainer at room temperature but develop a high enough pressure whenthe MDI is activated to deliver the drug as an atomised formulation evenat low ambient temperatures. Further, the propellant should be of lowacute and chronic toxicity and have a high cardiac sensitisationthreshold. It should have a high degree of chemical stability in contactwith the drug, the container and the metallic and non-metalliccomponents of the MDI device, and have a low propensity to extract lowmolecular weight substances from any elastomeric materials in the MDIdevice. The propellant should also be capable of maintaining the drug ina homogeneous solution, in a stable suspension or in a stable dispersionfor a sufficient time to permit reproducible delivery of the drug inuse. When the drug is in suspension in the propellant, the density ofthe liquid propellant is desirably similar to that of the solid drug inorder to avoid rapid sinking or floating of the drug particles in theliquid. Finally, the propellant should not present a significantflammability risk to the patient in use. In particular, it should form anon-flammable or low flammability mixture when mixed with air in therespiratory tract.

Dichlorodifluoromethane (R-12) possesses a suitable combination ofproperties and was for many years the most widely used MDI propellant,often blended with trichlorofluoromethane (R-11). Due to internationalconcern that fully and partially halogenated chlorofluorocarbons (CFCs),such as dichlorodifluoromethane and trichlorofluoromethane, weredamaging the earth's protective ozone layer, many countries entered intoan agreement, the Montreal Protocol, stipulating that their manufactureand use should be severely restricted and eventually phased outcompletely. Dichlorodifluoromethane and trichlorofluoromethane werephased out for refrigeration use in the 1990's, but are still used insmall quantities in the MDI sector as a result of an essential useexemption in the Montreal Protocol.

1,1,1,2-tetrafluoroethane (HFA-134a) was introduced as a replacementrefrigerant and MDI propellant for R-12.1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) was also introduced as areplacement propellant for dichlorotetrafluoroethane (R-114) in the MDIsector and is sometimes used alone or blended with HFA-134a for thisapplication.

Although HFA-134a and HFA-227ea have low ozone depletion potentials(ODPs), they have global warming potentials (GWPs), 1430 and 3220respectively, which are now considered to be too high by some regulatorybodies, especially for dispersive uses when they are released into theatmosphere.

One industrial area that has received particular attention recently hasbeen the automotive air-conditioning sector where the use of HFA-134ahas come under regulatory control as a result of the European Mobile AirConditioning Directive (2006/40/EC). Industry is developing a number ofpossible alternatives to HFA-134a in automotive air conditioning andother applications that have a low greenhouse warming potential (GWP) aswell as a low ozone depletion potential (ODP). Many of thesealternatives include hydrofluoropropenes, especially thetetrafluoropropenes, such as 2,3,3,3-tetrafluoropropene (HFO-1234yf) and1,3,3,3-tetrafluoropropene (HFO-1234ze).

Although the proposed alternatives to HFA-134a have a low GWP, thetoxicological status of many of the components, such as certain of thefluoropropenes, is unclear and they are unlikely to be acceptable foruse in the MDI sector for many years, if at all.

Glycopyrrolate (also known as glycopyrronium) is a long actingmuscarinic antagonist (LAMA) that is used in the treatment of COPD. Itis typically used as part of a combination therapy in which the drugcomponent also includes a long acting beta-2 agonist (LABA).

Unfortunately, it has proven difficult to formulate glycopyrrolate in aform that is suitable for delivery using a MDI due to its limitedphysical and chemical stability. This problem has been addressed in thepast by incorporating an acid stabilizer, such as an organic orinorganic acid, in the drug formulation. However, the use of acidstabilizers in the drug formulation necessitates the use of expensivecoated cans to hold the formulation if corrosion problems are to beavoided.

There is a need for a pharmaceutical composition of glycopyrrolate whichcan be delivered using a MDI and that uses a propellant having a reducedGWP in comparison with HFA-134a and HFA-227ea. There is also a need fora pharmaceutical composition which exhibits satisfactory stabilitywithout the use of acid stabilizers.

DETAILED DESCRIPTION

We have found that the issues associated with the use ofglycopyrrolate-based formulations in MDIs may be overcome by using apropellant that comprises 1,1-difluoroethane (HFA-152a), particularlywhere the formulations contain low amounts of water. These formulationscan exhibit improved chemical stability, improved aerosolisationperformance for improved drug delivery, good suspension stability,reduced GWP, good compatibility with standard uncoated aluminium cans aswell as good compatibility with standard valves and seals.

According to a first aspect of the present invention, there is provideda pharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the first aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. The improved chemical stability isobserved, in particular, when the pharmaceutical composition containsless than 100 ppm, preferably less than 50 ppm, more preferably lessthan 10 ppm and particularly less than 5 ppm of water based on the totalweight of the pharmaceutical composition. In referring to the watercontent of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of water, e.g. greater than 1 ppm, but less than the amountsdiscussed above, as it can in practice be difficult to remove all thewater from the composition and then retain it in such a water-freestate.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a),    -   wherein the composition contains less than 100 ppm, preferably        less than 50 ppm, more preferably less than 10 ppm and        especially less than 5 ppm of water based on the total weight of        the pharmaceutical composition.

In a preferred embodiment, the pharmaceutical composition of the firstaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the first aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Accordingly a preferred embodiment of the first aspect of the presentinvention provides a pharmaceutical composition, e.g. a pharmaceuticalsuspension or a pharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a),    -   wherein the composition contains less than 1000 ppm, preferably        less than 500 ppm, more preferably less than 100 ppm and        especially less than 50 ppm of oxygen based on the total weight        of the pharmaceutical composition.

The pharmaceutical composition of the present invention is suitable fordelivery to the respiratory tract using a metered dose inhaler (MDI).

The at least one pharmaceutically acceptable salt of glycopyrrolate inthe pharmaceutical composition of the invention in all aspects andembodiments disclosed herein is preferably in a micronized form.Further, the pharmaceutical composition of the invention in all aspectsand embodiments disclosed herein is preferably free of perforatedmicrostructures.

The at least one pharmaceutically acceptable salt of glycopyrrolate maybe dispersed or suspended in the propellant. The drug particles in suchsuspensions preferably have a diameter of less than 100 microns, e.g.less than 50 microns. However, in an alternative embodiment thepharmaceutical compositions of the invention are solutions with the atleast one pharmaceutically acceptable salt of glycopyrrolate dissolvedin the propellant, e.g. with the assistance of a polar excipient, suchas ethanol.

The pharmaceutical composition of the first aspect of the inventionincludes a pharmaceutically acceptable salt of glycopyrrolate (alsoknown as glycopyrronium). Glycopyrrolate is a quaternary ammonium salt.Suitable pharmaceutically acceptable counter ions include, for example,fluoride, chloride, bromide, iodide, nitrate, sulfate, phosphate,formate, acetate, trifluoroacetate, propionate, butyrate, lactate,citrate, tartrate, malate, maleate, succinate, benzoate,p-chlorobenzoate, diphenyl-acetate or triphenylacetate,o-hydroxybenzoate, p-hydroxybenzoate,1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,methanesulfonate and benzenesulfonate. A preferred compound is thebromide salt of glycopyrrolate also known as glycopyrronium bromide.

Accordingly, in the above described pharmaceutical compositions of theinvention, the at least one pharmaceutically acceptable salt ofglycopyrrolate is preferably glycopyrronium bromide.

The amount of the drug component in the pharmaceutical composition ofthe first aspect of the present invention will typically be in the rangeof from 0.01 to 2.5 weight % based on the total weight of thepharmaceutical composition. Preferably, the drug component will comprisefrom 0.01 to 2.0 weight %, more preferably from 0.05 to 2.0 weight % andespecially from 0.05 to 1.5 weight % of the total weight of thepharmaceutical composition. The drug component may consist essentiallyof or consist entirely of the at least one pharmaceutically acceptablesalt of glycopyrrolate. By the term “consists essentially of”, we meanthat at least 98 weight %, more preferably at least 99 weight % andespecially at least 99.9 weight % of the drug component consists of theleast one pharmaceutically acceptable salt of glycopyrrolate.Alternatively, the drug component may contain other drugs, such as atleast one long acting beta-2 agonist (LABA) and/or at least onecorticosteroid.

The propellant component in the pharmaceutical composition of the firstaspect of the present invention comprises 1,1-difluoroethane (HFA-152a).Thus, we do not exclude the possibility that the propellant componentmay include other propellant compounds in addition to the HFA-152a. Forexample, the propellant component may additionally comprise one or moreadditional hydrofluorocarbon or hydrocarbon propellant compounds, e.g.selected from HFA-227ea, HFA-134a, difluoromethane (HFA-32), propane,butane, isobutane and dimethyl ether. The preferred additionalpropellants are HFA-227ea and HFA-134a.

If an additional propellant compound is included, such as HFA-134a orHFA-227ea, at least 5% by weight, preferably at least 10% by weight andmore preferably at least 50% by weight of the propellant componentshould be HFA-152a. Typically, the HFA-152a will constitute at least 90weight %, e.g. from 90 to 99 weight %, of the propellant component.Preferably, the HFA-152a will constitute at least 95 weight %, e.g. from95 to 99 weight %, and more preferably at least 99 weight % of thepropellant component.

In a preferred embodiment, the propellant component has a global warmingpotential (GWP) of less than 250, more preferably less than 200 andstill more preferably less than 150.

In an especially preferred embodiment, the propellant component consistsentirely of HFA-152a so that the pharmaceutical composition of theinvention comprises HFA-152a as the sole propellant. By the term“consists entirely of” we do not, of course, exclude the presence ofminor amounts, e.g. up to a few hundred parts per million, of impuritiesthat may be present following the process that is used to make theHFA-152a providing that they do not affect the suitability of thepropellant in medical applications. Preferably the HFA-152a propellantwill contain no more than 10 ppm, e.g. from 0.5 to 10 ppm, morepreferably no more than 5 ppm, e.g. from 1 to 5 ppm, of unsaturatedimpurities, such as vinyl fluoride, vinyl chloride, vinylidene fluorideand chloro-fluoro ethylene compounds.

The amount of propellant component in the pharmaceutical composition ofthe invention will vary depending on the amounts of the drugs and othercomponents in the pharmaceutical composition. Typically, the propellantcomponent will comprise from 80.0 to 99.99 weight % of the total weightof the pharmaceutical composition. Preferably, the propellant componentwill comprise from 90.0 to 99.99 weight %, more preferably from 96.5 to99.99 weight % and especially from 97.5 to 99.95 weight % of the totalweight of the pharmaceutical composition.

In one embodiment, the pharmaceutical composition of the first aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the firstaspect of the present invention additionally includes a polar excipient,such as ethanol. Polar excipients have been used previously inpharmaceutical compositions for treating respiratory disorders that aredelivered using metered dose inhalers (MDIs). They are also referred toas solvents, co-solvents, carrier solvents and adjuvants. Theirinclusion can serve to solubilise the surfactant or the drug in thepropellant and/or inhibit deposition of drug particles on the surfacesof the metered dose inhaler that are contacted by the pharmaceuticalcomposition as it passes from the container in which it is stored to thenozzle outlet. They are also used as bulking agents in two-stage fillingprocesses where the drug is mixed with a suitable polar excipient. Themost commonly used polar excipient is ethanol. If a polar excipient isused, it will typically be present in an amount of from 0.5 to 10% byweight, preferably in an amount of from 1 to 5% by weight based on thetotal weight of the pharmaceutical composition.

In one preferred embodiment, the pharmaceutical composition of thepresent invention is free of polar excipients such as ethanol.

The pharmaceutical composition of the first aspect of the presentinvention may also include a surfactant component comprising at leastone surfactant compound. Surfactant compounds of the type that have beenin use hitherto in pharmaceutical formulations for MDIs may be used inthe pharmaceutical compositions of the present invention. Preferredsurfactants are selected from polyvinylpyrrolidone, polyethylene glycolsurfactants, oleic acid and lecithin. By the term oleic acid, we are notnecessarily referring to pure (9Z)-octadec-9-enoic acid. When sold forsurfactant use in medical applications, oleic acid is typically amixture of several fatty acids, with (9Z)-octadec-9-enoic acid being thepredominant fatty acid, e.g. present in an amount of at least 65 weight% based on the total weight of the surfactant.

In a preferred embodiment, the surfactant component consists essentiallyof and still more preferably consists entirely of at least onesurfactant compound selected from polyvinylpyrrolidone, polyethyleneglycols, oleic acid and lecithin. In a particularly preferredembodiment, the surfactant component consists essentially of and stillmore preferably consists entirely of at least one surfactant compoundselected from polyvinylpyrrolidone and polyethylene glycols. By the term“consists essentially of”, we mean that at least 95 weight %, morepreferably at least 98 weight % and especially at least 99 weight % ofthe surfactant component is composed of the listed surfactants.

If a surfactant component is used, it will typically be present in anamount of from 0.1 to 2.5% by weight, preferably in an amount of from0.2 to 1.5% by weight based on the total weight of the pharmaceuticalcomposition.

In a preferred embodiment, the pharmaceutical composition of the firstaspect of the present invention is free of acid stabilisers, such asorganic and inorganic acids.

The pharmaceutical composition of the invention may also include a longacting beta-2-agonist (LABA). Any of the long acting beta-2-agoniststhat have been in use hitherto for treating asthma and chronicobstructive pulmonary diseases and that can be delivered using a MDI canbe used in the pharmaceutical compositions of the present invention.Suitable long acting beta-2-agonists include formoterol, arformoterol,bambuterol, clenbuterol, salmeterol, indacaterol, olodaterol andvilanterol as well as their pharmaceutically acceptable derivatives,such as their pharmaceutically acceptable salts. Preferred compoundsinclude indacaterol, olodaterol, formoterol and vilanterol and thepharmaceutically acceptable salts thereof. Particularly preferredcompounds are indacaterol and the pharmaceutically acceptable saltsthereof, especially indacaterol maleate.

Accordingly, a second aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide, and at least one long acting beta-2-agonist (LABA),    especially at least one long acting beta-2 agonist (LABA) selected    from indacaterol, olodaterol, formoterol, vilanterol and the    pharmaceutically acceptable salts thereof; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the second aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the second aspect of the present invention contains lessthan 100 ppm, more preferably less than 50 ppm, particularly less than10 ppm and especially less than 5 ppm of water based on the total weightof the pharmaceutical composition. It has been found that small amountsof water alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the second aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the second aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the secondaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the second aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred glycopyrrolate salts are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the second aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onepharmaceutically acceptable salt of glycopyrrolate and the at least onelong acting beta-2 agonist (LABA). By the term “consists essentiallyof”, we mean that at least 98 weight %, more preferably at least 99weight % and especially at least 99.9 weight % of the drug componentconsists of the at least one pharmaceutically acceptable salt ofglycopyrrolate and the at least one long acting beta-2 agonist (LABA).

In one embodiment, the pharmaceutical composition of the second aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the secondaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the second aspect of theinvention, the drug component comprises glycopyrronium bromide and atleast one long acting beta-2-agonist (LABA) selected from indacaterol,olodaterol, formoterol, vilanterol and the pharmaceutically acceptablesalts thereof, especially indacaterol and indacaterol maleate.Preferably, the glycopyrronium bromide and the at least one selectedlong acting beta-2-agonist are the only pharmaceutical actives in thepharmaceutical composition of the second aspect of the invention.

In a preferred embodiment, the pharmaceutical composition of the secondaspect of the present invention is free of acid stabilisers, such asorganic and inorganic acids.

The pharmaceutical composition of the invention may also include acorticosteroid. Any of the corticosteroids that have been in usehitherto for treating asthma and chronic obstructive pulmonary diseasesand that can be delivered using a MDI can be used in the pharmaceuticalcompositions of the present invention. Suitable corticosteroids includebudesonide, mometasone, beclomethasone and fluticasone as well as theirpharmaceutically acceptable derivatives, such as their pharmaceuticallyacceptable salts. Preferred compounds include budesonide,beclomethasone, beclomethasone dipropionate, fluticasone furoate andfluticasone propionate.

Accordingly, a third aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide, and at least one corticosteroid, particularly at least one    corticosteroid selected from fluticasone, budesonide, mometasone and    beclomethasone and the pharmaceutically acceptable salts thereof;    and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the third aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the third aspect of the present invention contains lessthan 100 ppm, more preferably less than 50 ppm, particularly less than10 ppm and especially less than 5 ppm of water based on the total weightof the pharmaceutical composition. It has been found that small amountsof water alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the third aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the third aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the thirdaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the third aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred glycopyrrolate salts are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the third aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onepharmaceutically acceptable salt of glycopyrrolate and the at least onecorticosteroid. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the drug component consists of the least onepharmaceutically acceptable salt of glycopyrrolate and the at least onecorticosteroid.

In one embodiment, the pharmaceutical composition of the third aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the thirdaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the third aspect of theinvention, the drug component comprises glycopyrronium bromide and atleast one corticosteroid selected from budesonide, beclomethasone,beclomethasone dipropionate, fluticasone furoate and fluticasonepropionate. Preferably, the glycopyrronium bromide and the at least oneselected corticosteroid are the only pharmaceutical actives in thepharmaceutical composition of the third aspect of the invention.

In a preferred embodiment, the pharmaceutical composition of the thirdaspect of the present invention is free of acid stabilisers, such asorganic and inorganic acids.

The pharmaceutical composition of the invention may also include a longacting beta-2-agonist (LABA) and a corticosteroid. Any of the longacting beta-2-agonists and corticosteroids that have been in usehitherto for treating asthma and chronic obstructive pulmonary diseasesand that can be delivered using a MDI can be used in the pharmaceuticalcompositions of the present invention. Suitable and preferred longacting beta-2-agonists are as discussed above for the second aspect ofthe invention. Suitable and preferred corticosteroids are as discussedabove for the third aspect of the present invention.

Accordingly, a fourth aspect of the present invention provides apharmaceutical composition, e.g. a pharmaceutical suspension or apharmaceutical solution, said composition comprising:

-   (i) a drug component comprising at least one pharmaceutically    acceptable salt of glycopyrrolate, especially glycopyrronium    bromide, at least one long acting beta-2-agonist (LABA), especially    at least one long acting beta-2 agonist (LABA) selected from    indacaterol, olodaterol, formoterol, vilanterol and the    pharmaceutically acceptable salts thereof and at least one    corticosteroid, particularly at least one corticosteroid selected    from fluticasone, budesonide, mometasone and beclomethasone and the    pharmaceutically acceptable salts thereof; and-   (ii) a propellant component comprising 1,1-difluoroethane    (HFA-152a).

The pharmaceutical composition of the fourth aspect of the inventiontypically contains less than 500 ppm of water based on the total weightof the pharmaceutical composition. Preferably, the pharmaceuticalcomposition of the fourth aspect of the present invention contains lessthan 100 ppm, more preferably less than 50 ppm, particularly less than10 ppm and especially less than 5 ppm of water based on the total weightof the pharmaceutical composition. It has been found that small amountsof water alongside the use of HFA-152a as the propellant can result in apharmaceutical composition with improved chemical stability. Inreferring to the water content of the pharmaceutical composition, we arereferring to the content of free water in the composition and not anywater that happens to be present in any hydrated drug compounds that maybe used as part of the drug component. In an especially preferredembodiment, the pharmaceutical composition of the fourth aspect of thepresent invention is water-free. Alternatively, the pharmaceuticalcomposition of the fourth aspect may contain greater than 0.5 ppm ofwater, e.g. greater than 1 ppm, but less than the amounts discussedabove, as it can in practice be difficult to remove all the water fromthe composition and then retain it in such a water-free state.

In a preferred embodiment, the pharmaceutical composition of the fourthaspect of the invention contains less than 1000 ppm, preferably lessthan 500 ppm, more preferably less than 100 ppm and particularly lessthan 50 ppm of dissolved oxygen based on the total weight of thepharmaceutical composition. In an especially preferred embodiment, thepharmaceutical composition is oxygen-free. Alternatively, thepharmaceutical composition of the fourth aspect may contain greater than0.5 ppm of oxygen, e.g. 1 ppm or greater, but less than the amountsdiscussed above, as it can in practice be difficult to retain thecomposition in an oxygen-free state. Low oxygen contents are preferredbecause they tend to reduce the degradation of the drug compoundsresulting in a composition with higher chemical stability.

Suitable and preferred glycopyrrolate salts are as discussed above forthe pharmaceutical composition of the first aspect of the presentinvention.

Typical and preferred amounts of the drug component and the propellantcomponent in the pharmaceutical composition of the fourth aspect of thepresent invention and suitable, typical and preferred compositions forthe propellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. The drug component mayconsist essentially of or consist entirely of the at least onepharmaceutically acceptable salt of glycopyrrolate, the at least onelong acting beta-2 agonist (LABA) and the at least one corticosteroid.By the term “consists essentially of”, we mean that at least 98 weight%, more preferably at least 99 weight % and especially at least 99.9weight % of the drug component consists of the least onepharmaceutically acceptable salt of glycopyrrolate, the at least onelong acting beta-2 agonist (LABA) and the at least one corticosteroid.

In one embodiment, the pharmaceutical composition of the fourth aspectof the present invention consists essentially of and more preferablyconsists entirely of the two components (i) and (ii) listed above. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the pharmaceutical composition consists of the two listedcomponents.

In another embodiment, the pharmaceutical composition of the fourthaspect of the invention may contain one or both of a polar excipient anda surfactant component as discussed above for the pharmaceuticalcomposition of the first aspect of the invention. Suitable and preferredpolar excipients and surfactants are as discussed above for thepharmaceutical composition of the first aspect of the invention. Typicaland preferred amounts of the polar excipient and the surfactantcomponent are as discussed above for the pharmaceutical composition ofthe first aspect of the invention.

In an especially preferred embodiment of the fourth aspect of theinvention, the drug component comprises glycopyrronium bromide, at leastone long acting beta-2-agonist (LABA) selected from indacaterol,olodaterol, formoterol, vilanterol and the pharmaceutically acceptablesalts thereof, especially indacaterol and indacaterol maleate, and atleast one corticosteroid selected from budesonide, beclomethasone,beclomethasone dipropionate, fluticasone furoate and fluticasonepropionate. Preferably, the glycopyrronium bromide, the at least oneselected long acting beta-2-agonist and the at least one selectedcorticosteroid are the only pharmaceutical actives in the pharmaceuticalcomposition of the fourth aspect of the invention.

In a preferred embodiment, the pharmaceutical composition of the fourthaspect of the present invention is free of acid stabilisers, such asorganic and inorganic acids.

It has been found that the use of propellants comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containinga glycopyrrolate salt, such as glycopyrronium bromide, and thepropellant can unexpectedly improve the chemical stability of theglycopyrrolate compound compared to the stability it exhibits informulations containing either HFA-134a or HFA-227ea as the propellant.

Accordingly, in a fifth aspect of the present invention there isprovided a method of improving the stability of a pharmaceuticalcomposition comprising a propellant component and a drug componentcomprising at least one pharmaceutically acceptable salt ofglycopyrrolate, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the stabilisation method of the fifthaspect of the present invention may be a suspension or a solution.

The improved chemical stability can result, in particular, when thepharmaceutical composition contains less than 500 ppm, preferably lessthan 100 ppm, more preferably less than 50 ppm, still more preferablyless than 10 ppm and particularly less than 5 ppm of water based on thetotal weight of the pharmaceutical composition. In referring to thewater content of the pharmaceutical composition, we are referring to thecontent of free water in the composition and not any water that happensto be present in any hydrated drug compounds that may be used as part ofthe drug component. In an especially preferred embodiment, thepharmaceutical composition is water-free. Alternatively, thepharmaceutical composition recited in the fifth aspect of the presentinvention may contain greater than 0.5 ppm of water, e.g. greater than 1ppm, but less than the amounts discussed above, as it can in practice bedifficult to remove all the water from the composition and then retainit in such a water-free state.

Accordingly, in a preferred embodiment of the fifth aspect of thepresent invention there is provided a method of improving the stabilityof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one pharmaceutically acceptable saltof glycopyrrolate, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a) and selecting the componentsand conditions for the preparation of the pharmaceutical composition tomaintain the water content of the pharmaceutical composition below 100ppm, preferably below 50 ppm, more preferably below 10 ppm andparticularly below 5 ppm based on the total weight of the pharmaceuticalcomposition.

In practice, preparing a pharmaceutical composition with the low waterlevels recited above involves using a propellant component with asuitably low water content, as it is usually the largest mass item inthe finished device, and then preparing the pharmaceutical compositionunder suitably dry conditions, e.g. in a dry nitrogen atmosphere.Preparing pharmaceutical compositions under dry conditions is well knownand the techniques involved are well understood by those skilled in theart. Other steps to obtain a low water content in the finished deviceinclude drying and storing the can and valve components in amoisture-controlled atmosphere, e.g. dry nitrogen or air, prior to andduring device assembly. If the pharmaceutical composition contains asignificant amount of ethanol, then it may also be important to controlthe water content of the ethanol as well as the propellant, e.g. bydrying to reduce the water content to suitably low levels. Suitabledrying techniques are well known to those skilled in the art and includethe use of a molecular sieve or other inorganic desiccant and membranedrying processes.

In the stabilisation method of the fifth aspect of the present inventionsuitable and preferred glycopyrrolate salts are as described above forthe pharmaceutical composition of the first aspect of the presentinvention. In addition, typical and preferred amounts of the drugcomponent and the propellant component in the stabilisation method ofthe fifth aspect of the present invention and suitable, typical andpreferred compositions for the propellant component are as discussedabove for the pharmaceutical composition of the first aspect of theinvention.

The drug component in the stabilisation method of the fifth aspect ofthe present invention may consist essentially of or consist entirely ofthe at least one pharmaceutically acceptable salt of glycopyrrolate. Bythe term “consists essentially of”, we mean that at least 98 weight %,more preferably at least 99 weight % and especially at least 99.9 weight% of the drug component consists of the least one glycopyrrolate salt.Alternatively, the drug component may additionally comprise at least onecorticosteroid and/or at least one long acting beta-2-agonist. When acorticosteroid and/or a long acting beta-2-agonist are included,suitable and preferred corticosteroids and suitable and preferred longacting beta-2-agonists are as described above for the pharmaceuticalcompositions of the second and third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the fifth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thefifth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

In a preferred embodiment, the pharmaceutical composition that isprovided in the stabilisation method of the fifth aspect of the presentinvention is free of acid stabilisers, such as organic and inorganicacids.

In one preferred stabilisation method, the resulting pharmaceuticalcomposition after storage at 25° C. and 60% relative humidity for 3months will produce less than 1.0% by weight, preferably less than 0.8%by weight and more preferably less than 0.6% by weight of impuritiesfrom the degradation of the at least one pharmaceutically acceptablesalt of glycopyrrolate based on the total weight of the at least onepharmaceutically acceptable salt of glycopyrrolate and the impurities.

In another preferred stabilisation method, the resulting pharmaceuticalcomposition after storage at 40° C. and 75% relative humidity for 3months will produce less than 1.2% by weight, preferably less than 1.0%by weight and more preferably less than 0.8% by weight of impuritiesfrom the degradation of the at least one pharmaceutically acceptablesalt of glycopyrrolate based on the total weight of the at least onepharmaceutically acceptable salt of glycopyrrolate and the impurities.

In yet another preferred stabilisation method in which thepharmaceutical composition also comprises at least one corticosteroidand/or at least one long acting beta-2-agonist, the resultingpharmaceutical composition after storage at 25° C. and 60% relativehumidity for 3 months will produce less than 1.0% by weight, preferablyless than 0.8% by weight and more preferably less than 0.6% by weight ofimpurities from the degradation of the at least one pharmaceuticallyacceptable salt of glycopyrrolate based on the total weight of the atleast one pharmaceutically acceptable salt of glycopyrrolate and theimpurities.

In still another preferred stabilisation method in which thepharmaceutical composition also comprises at least one corticosteroidand/or at least one long acting beta-2-agonist, the resultingpharmaceutical composition after storage at 40° C. and 75% relativehumidity for 3 months will produce less than 1.2% by weight, preferablyless than 1.0% by weight and more preferably less than 0.8% by weight ofimpurities from the degradation of the at least one pharmaceuticallyacceptable salt of glycopyrrolate based on the total weight of the atleast one pharmaceutically acceptable salt of glycopyrrolate and theimpurities.

In yet another preferred stabilisation method, at least 95.0% by weight,preferably at least 96.0% by weight and more preferably at least 97.0%by weight of the at least one pharmaceutically acceptable salt ofglycopyrrolate that is contained originally in the pharmaceuticalcomposition immediately following preparation will be present in thecomposition after storage at 25° C. and 60% relative humidity for 3months and after storage at 40° C. and 75% relative humidity for 3months.

In still another preferred stabilisation method in which thepharmaceutical composition also comprises at least one corticosteroidand/or at least one long acting beta-2-agonist, at least 95.0% byweight, preferably at least 96.0% by weight and more preferably at least97.0% by weight of the at least one pharmaceutically acceptable salt ofglycopyrrolate that is contained originally in the pharmaceuticalcomposition immediately following preparation will be present in thecomposition after storage at 25° C. and 60% relative humidity for 3months and after storage at 40° C. and 75% relative humidity for 3months.

In a further preferred stabilisation method, at least 95.0%, preferablyat least 96.0% and more preferably at least 97.0% of the originalpharmaceutical activity of the composition is retained after storage at25° C. and 60% relative humidity for 3 months and after storage at 40°C. and 75% relative humidity for 3 months.

One preferred pharmaceutical composition of the first, second, third andfourth aspects of the present invention will produce less than 1.0% byweight, preferably less than 0.8% by weight and more preferably lessthan 0.6% by weight of total impurities from the degradation of the atleast one pharmaceutically acceptable salt of glycopyrrolate afterstorage at 25° C. and 60% relative humidity for 3 months.

Another preferred pharmaceutical composition of the first, second, thirdand fourth aspects of the present invention will produce less than 1.2%by weight, preferably less than 1.0% by weight and more preferably lessthan 0.8% by weight of total impurities from the degradation of the atleast one pharmaceutically acceptable salt of glycopyrrolate afterstorage at 40° C. and 75% relative humidity for 3 months.

The weight % of impurities indicated above are based on the total weightof the at least one pharmaceutically acceptable salt of glycopyrrolateand the impurities.

In a further preferred pharmaceutical composition of the first, second,third and fourth aspects of the present invention at least 95.0% byweight, preferably at least 96.0% by weight and more preferably at least97.0% by weight of the at least one pharmaceutically acceptable salt ofglycopyrrolate that is contained originally in the pharmaceuticalcomposition of the invention immediately following preparation will bepresent in the composition after storage at 25° C. and 60% relativehumidity for 3 months and after storage at 40° C. and 75% relativehumidity for 3 months.

In yet another preferred pharmaceutical composition of the first,second, third and fourth aspects of the present invention at least95.0%, preferably at least 96.0% and more preferably at least 97.0% ofthe original pharmaceutical activity of the pharmaceutical compositionof the invention is retained after storage at 25° C. and 60% relativehumidity for 3 months and after storage at 40° C. and 75% relativehumidity for 3 months.

In referring to the storage of the pharmaceutical compositions in theabove described stabilisation methods, we are referring, in particular,to the storage of those compositions in uncoated aluminium containers.Similarly, in referring to the storage of the above describedpharmaceutical compositions, we are referring, in particular, to theirstorage in uncoated aluminium containers.

It has been found that the use of a propellant comprising1,1-difluoroethane (HFA-152a) in pharmaceutical compositions containinga glycopyrrolate salt, such as glycopyrronium bromide, and thepropellant that are designed to be delivered using a metered doseinhaler can unexpectedly improve the aerosolization performance of thepharmaceutical composition when that composition is delivered from themetered dose inhaler compared to the performance that is observed wheneither HFA-134a or HFA-227ea is used as the propellant. In particular,the fine particle fraction of the glycopyrrolate salt in the emitteddose typically comprises at least 35 weight %, preferably at least 40weight % and more preferably at least 45 weight % of the emitted dose ofthe glycopyrrolate salt. The fine particle fractions of theglycopyrrolate salt in the emitted dose are not only observedimmediately after the pharmaceutical composition has been filled into aMDI canister and prior to any long term storage, but also after storageunder stress storage conditions, e.g. after storage for 1 month at 40°C. and 75% relative humidity.

Accordingly, in a sixth aspect of the present invention there isprovided a method of improving the aerosolization performance of apharmaceutical composition comprising a propellant component and a drugcomponent comprising at least one pharmaceutically acceptable salt ofglycopyrrolate, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a).

The pharmaceutical composition in the method of the sixth aspect of thepresent invention may be a suspension or a solution.

In a preferred embodiment of the sixth aspect of the present inventionthere is provided a method of improving the aerosolization performanceof a pharmaceutical composition comprising a propellant component and adrug component comprising at least one pharmaceutically acceptable saltof glycopyrrolate, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a) and providing a pharmaceuticalcomposition which when delivered from a metered dose inhaler yields afine particle fraction of the at least one pharmaceutically acceptablesalt of glycopyrrolate which is at least 35 weight %, preferably atleast 40 weight % and more preferably at least 45 weight % of theemitted dose of the at least one pharmaceutically acceptable salt ofglycopyrrolate.

Increasing the fine particle fraction of the emitted dose is highlybeneficial, because it is the fine drug particles that are able topenetrate into the deep bronchiole passages and the alveolar passages ofthe lung to maximise relief from the effects of an asthma attack orCOPD.

The fine particle fraction is a widely recognised term in the art. It isa measure of the mass fraction of emitted aerosol particles having adiameter below 5 μm which is generally accepted as being the mostdesirable particle size range for effective alveolar drug delivery.

In the method of the sixth aspect of the present invention suitable andpreferred glycopyrrolate salts are as described above for thepharmaceutical composition of the first aspect of the present invention.In addition, typical and preferred amounts of the drug component and thepropellant component in the method of the sixth aspect of the presentinvention and suitable, typical and preferred compositions for thepropellant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

The drug component in the method of the sixth aspect of the presentinvention may consist essentially of or consist entirely of the at leastone glycopyrrolate salt, such as glycopyrronium bromide. By the term“consists essentially of”, we mean that at least 98 weight %, morepreferably at least 99 weight % and especially at least 99.9 weight % ofthe drug component consists of the least one glycopyrrolate salt.Alternatively, the drug component may additionally comprise at least onecorticosteroid and/or at least one long acting beta-2 agonist. When acorticosteroid and/or a long acting beta-2 agonist are included,suitable and preferred corticosteroids and suitable and preferred longacting beta-2 agonists are as described above for the pharmaceuticalcompositions of the second and third aspects of the present invention.

In one embodiment, the pharmaceutical composition in the sixth aspect ofthe present invention consists essentially of and more preferablyconsists entirely of the drug component and the propellant component asdefined above. By the term “consists essentially of”, we mean that atleast 98 weight %, more preferably at least 99 weight % and especiallyat least 99.9 weight % of the pharmaceutical composition consists of thetwo components.

In an alternative embodiment, the pharmaceutical composition in thesixth aspect of the invention may contain one or both of a polarexcipient and a surfactant component as discussed above for thepharmaceutical composition of the first aspect of the invention.Suitable and preferred polar excipients and surfactants are as discussedabove for the pharmaceutical composition of the first aspect of theinvention. Typical and preferred amounts of the polar excipient and thesurfactant component are as discussed above for the pharmaceuticalcomposition of the first aspect of the invention.

In a particularly preferred embodiment of the sixth aspect of thepresent invention, the drug component comprises glycopyrronium bromide,indacaterol and fluticasone propionate and the fine particle fraction ofeach drug in the emitted dose is at least 35 weight %, preferably atleast 40 weight % and more preferably at least 45 weight % of theemitted dose of that drug. The fine particle fractions of theglycopyrronium bromide, indacaterol and fluticasone propionate in theemitted dose are not only observed immediately after the pharmaceuticalcomposition has been filled into a MDI canister and prior to any longterm storage, but also after storage under stress storage conditions,e.g. after storage for 1 month at 40° C. and 75% relative humidity.Further, in this preferred embodiment it has surprisingly been foundthat the ratios of the three drugs as formulated can be substantiallyretained in the emitted dose unlike when HFA-134a is used as thepropellant.

The pharmaceutical compositions of the invention find particular utilityin the delivery of the glycopyrrolate salts, and where included thecorticosteroid and long acting beta-2 agonist compounds, from apressurised aerosol container, e.g. using a metered dose inhaler (MDI).For this application, the pharmaceutical compositions are contained inthe pressurised aerosol container and the HFA-152a propellant functionsto deliver the drug as a fine aerosol spray.

The pharmaceutical compositions of the invention may comprise one ormore other additives of the type that are conventionally used in drugformulations for pressurised MDIs, such as valve lubricants. Where otheradditives are included in the pharmaceutical compositions, they arenormally used in amounts that are conventional in the art.

The pharmaceutical compositions of the invention are normally stored ina pressurised container or canister which is to be used in associationwith a medication delivery device. When so stored, the pharmaceuticalcompositions are normally a liquid. In a preferred embodiment, thepressurised container is designed for use in a metered dose inhaler(MDI). In a particularly preferred embodiment, the pressurised containeris a coated aluminium can or an uncoated aluminium can, especially thelatter.

Accordingly, a seventh aspect of the present invention provides apressurised container holding the pharmaceutical composition of thefirst, second, third or fourth aspect of the present invention. In aneighth aspect, the present invention provides a medication deliverydevice, especially a metered dose inhaler, having a pressurisedcontainer holding the pharmaceutical composition of the first, second,third or fourth aspect of the present invention.

The metered dose inhaler typically comprises a nozzle and valve assemblythat is crimped to a container holding the pharmaceutical composition tobe dispensed. An elastomeric gasket is used to provide a seal betweenthe container and the nozzle/valve assembly. Preferred elastomericgasket materials are EPDM, chlorobutyl, bromobutyl and cycloolefincopolymer rubbers as these can exhibit good compatibility with HFA-152aand also provide a good barrier to prevent or limit HFA-152a permeatingfrom the container.

The pharmaceutical compositions of the present invention are for use inmedicine for treating a patient suffering or likely to suffer from arespiratory disorder and especially asthma or a chronic obstructivepulmonary disease.

Accordingly, the present invention also provides a method for treating apatient suffering or likely to suffer from a respiratory disorder,especially asthma or a chronic obstructive pulmonary disease, whichcomprises administering to the patient a therapeutically orprophylactically effective amount of a pharmaceutical composition asdiscussed above. The pharmaceutical composition is preferably deliveredto the patient using a MDI.

The pharmaceutical compositions of the invention can be prepared and theMDI devices filled using techniques that are standard in the art, suchas pressure filling and cold filling. For example, the pharmaceuticalcompositions can be prepared by a simple blending operation in which theat least one glycopyrrolate salt, optionally the at least onecorticosteroid and/or the at least one long acting beta-2 agonist,optionally the surfactant component and the HFA-152a-containingpropellant are mixed together in the required proportions in a suitablemixing vessel. Mixing can be promoted by stirring as is common in theart. Conveniently, the HFA-152a-containing propellant is liquefied toaid mixing. If the pharmaceutical composition is made in a separatemixing vessel, it can then be transferred to pressurised containers forstorage, such as pressurised containers that are used as part ofmedication delivery devices and especially MDIs.

The pharmaceutical compositions of the invention can also be preparedwithin the confines of a pressurised container, such as an aerosolcanister or vial, from which the compositions are ultimately released asan aerosol spray using a medication delivery device, such as a MDI. Inthis method, a weighed amount of the at least one glycopyrrolate saltand optionally the at least one corticosteroid and/or at least one longacting beta-2 agonist compound, is introduced into the open container. Avalve is then crimped onto the container and the HFA-152a-containingpropellant component, in liquid form, introduced through the valve intothe container under pressure, optionally after first evacuating thecontainer through the valve. The surfactant component, if included, canbe mixed with the drug(s) or, alternatively, introduced into thecontainer after the valve has been fitted, either alone or as a premixwith the propellant component. The whole mixture can then be treated todisperse the drugs in the propellant/surfactant mixture, e.g. byvigorous shaking or using an ultrasonic bath. Suitable containers may bemade of plastics, metal, e.g. aluminium, or glass. Preferred containersare made of metal, especially aluminium which may be coated or uncoated.Uncoated aluminium containers are especially preferred.

The container may be filled with enough of the pharmaceuticalcomposition to provide for a plurality of dosages. The pressurizedaerosol canisters that are used in MDIs typically contain 50 to 150individual dosages.

The present invention also provides a method of reducing the globalwarming potential (GWP) of a pharmaceutical composition comprising adrug component comprising at least one pharmaceutically acceptable saltof glycopyrrolate, especially glycopyrronium bromide, and a propellantcomponent, said method comprising using a propellant componentcomprising 1,1-difluoroethane (HFA-152a). This method is applicable tothe preparation of all the pharmaceutical compositions disclosed hereinin all their aspects and embodiments.

Preferably, at least 90 weight %, more preferably at least 95 weight %and still more preferably at least 99 weight % of the propellantcomponent used is HFA-152a. In an especially preferred embodiment, thepropellant component used is entirely HFA-152a.

The propellant component that is used will preferably have a globalwarming potential (GWP) of less than 250, more preferably less than 200and still more preferably less than 150.

The present invention is now illustrated but not limited by thefollowing examples.

Example 1

A number of experiments were conducted to investigate the in vitroaerosolization performance of combination drug formulations ofglycopyrronium bromide, indacaterol and fluticasone propionate inmetered dose inhalers (MDIs) using either HFA-134a or HFA-152a as thepropellant.

Pharmaceutical formulations of glycopyrronium bromide, indacaterol andfluticasone propionate were prepared in either HFA-134a or HFA-152a(Mexichem, UK). The drugs were weighed directly into standard uncoated14 ml aluminium canisters (C128, Presspart, Blackburn, UK). Thecanisters were then crimped with a 50 μL valve (Bespak, Kings Lynn, UK)following which the propellant was filled into the canisters through thevalve using a manual Pamasol crimper/filler (Pamasol, Switzerland).Finally, the canisters were sonicated for 20 minutes to aid dispersionof the drug in the suspension. The nominal dose of glycopyrroniumbromide was 50 μg, the nominal dose of indacaterol was 100 μg and thenominal dose of fluticasone propionate was 125 μg.

The in vitro aerosolization performance of the formulations was testedimmediately after preparation (time t=zero) with a Next GenerationImpactor using the method described below. The formulations were thenstored under stress storage conditions (valve down) at 40° C. and 75%relative humidity for 1 month. After storing for 1 month under thestress storage conditions, the in vitro aerosolization performance ofthe pharmaceutical formulations was tested again as before with a NextGeneration Impactor using the method described below.

The Next Generation Impactor (NGI, Copley Scientific, Nottingham UK) wasconnected to a vacuum pump (GE Motors, NJ, USA). Prior to testing, thecups of the NGI system were coated with 1% v/v silicone oil in hexane toeliminate particle bounce. For each experiment, three actuations of thevalve were discharged into the NGI at 30 Lmin⁻¹ as per pharmacopeiaguidelines. Following aerosolization, the NGI apparatus was dismantledand the actuator and each part of the NGI was washed down into knownvolumes of the HPLC mobile phase. The mass of drug deposited on eachpart of the NGI was determined by HPLC. This protocol was repeated threetimes for each canister, following which, the fine particle dose (FPD)and fine particle fraction of the emitted dose (FPF_(ED)) weredetermined.

High performance liquid chromatography (HPLC) was used to determine drugcontent following aerosolization studies (see below). A 250 mm×4.6 mmHypersil ODS C18 column with a 5 μm particle size (Fisher, Loughborough)or an equivalent was used for the analysis of fluticasone propionate. A50 mm×4.6 mm Nucleosil 100-3 C₁₈ HD column with a 3 μm particle size oran equivalent was used for the analysis of glycopyrronium bromide andindacaterol.

The columns were coupled to a UV detector operating at a wavelength ofeither 220 nm or 235 nm depending on which drug was being analysed. Theautosampler was operated at ambient temperature and 100 μl samples wereinjected into the column for the analyses. The chromatographicconditions are shown in Tables 1 and 2 below.

TABLE 1 Pump UV Column Flow Wave- Temper- Rate Mobile length ature Drug(ml · min⁻¹) Phase (nm) (° C.) Fluticasone 1.5 Methanol, 235 40Propionate acetonitrile and water— 45:35:20 v/v

TABLE 2 Pump UV Column Flow Wave- Temper- Rate Mobile length ature Drug(ml · min⁻¹) Phase (nm) (° C.) Glycopyrronium 1.5 Mobile Phase 220 30Bromide and A: Buffer* and Indacaterol acetonitrile 75:25 v/v MobilePhase B: Buffer* and acetonitrile 25:75 v/v *Buffer is aqueoustriethylamine/Na₂HPO₄/H₃PO₄ at pH 2.5 The composition of the mobilephase was varied as shown in Table 3 below.

TABLE 3 Time Mobile Phase Mobile Phase (minutes) A (% v/v) B (% v/v) 0100 0 3.0 85 15 3.1 0 100 4.0 0 100 4.1 100 0 5.0 100 0

The results are shown in Tables 4 to 6 below.

TABLE 4 In vitro aerosolization performance of combination formulationsof glycopyrronium bromide, indacaterol and fluticasone propionatedelivered from a MDI with HFA-134a as the propellant at time t = 0 andafter storage (valve down) for 1 month at 40° C. and 75% relativehumidity as characterised by the emitted dose, fine particle dose, fineparticle fraction of the emitted dose (FPF_(ED) (%)), mass medianaerodynamic diameter (MMAD) and geometric standard deviation (GSD).Emitted Fine Particle MMAD ± Dose Dose FPF_(ED) GSD (μg ± S.D.) (μg ±S.D.) (%) (μm) Glycopyrronium  43.7 ± 0.2 12.6 ± 0.1 28.7 ± 0.2 2.6 ±2.4 Bromide (T = 0) Glycopyrronium  38.7 ± 0.6 11.4 ± 0.4 29.4 ± 0.5 2.8± 2.3 Bromide (T = 1 month @ 40° C./75% RH) Indacaterol (T = 0)  75.8 ±1.8 23.8 ± 0.8 31.5 ± 1.8 4.8 ± 1.9 Indacaterol (T = 1  73.7 ± 1.2 21.9± 0.7 29.8 ± 0.7 4.8 ± 1.9 month @ 40° C./75% RH) Fluticasone 119.0 ±2.0 38.8 ± 1.7 32.6 ± 0.9 3.0 ± 1.8 Propionate (T = 0) Fluticasone 112.8± 2.3 32.8 ± 1.9 29.0 ± 1.9 3.1 ± 1.9 Propionate (T = 1 month @ 40°C./75% RH)

TABLE 5 In vitro aerosolization performance of combination formulationsof glycopyrronium bromide, indacaterol and fluticasone propionatedelivered from a MDI with HFA-152a as the propellant at time t = 0 andafter storage (valve down) for 1 month at 40° C. and 75% relativehumidity as characterised by the emitted dose, fine particle dose, fineparticle fraction of the emitted dose (FPF_(ED) (%)), mass medianaerodynamic diameter (MMAD) and geometric standard deviation (GSD).Emitted Fine Particle MMAD ± Dose Dose FPF_(ED) GSD (μg ± S.D.) (μg ±S.D.) (%) (μm) Glycopyrronium  45.2 ± 0.7 21.0 ± 1.0 46.5 ± 2.9 3.1 ±2.2 Bromide (T = 0) Glycopyrronium  44.2 ± 0.6 20.7 ± 0.8 45.8 ± 1.8 3.0± 2.2 Bromide (T = 1 month @ 40° C./75% RH) Indacaterol (T = 0)  92.1 ±3.0 46.8 ± 1.5 50.9 ± 0.1 3.4 ± 1.9 Indacaterol (T = 1  90.8 ± 2.3 45.8± 1.2 49.5 ± 0.2 3.5 ± 2.0 month @ 40° C./75% RH) Fluticasone 111.8 ±0.7 51.5 ± 1.9 46.1 ± 1.5 3.0 ± 1.9 Propionate (T = 0) Fluticasone 105.6± 0.8 48.5 ± 1.5 45.2 ± 1.2 2.9 ± 1.9 Propionate (T = 1 month @ 40°C./75% RH)

TABLE 6 Ratio of glycopyrronium bromide, indacaterol and fluticasonepropionate in the delivered fine particle fraction using HFA-134apropellant and HFA-152a propellant at time t = 0 and after storage(valve down) for 1 month at 40° C. and 75% relative humidity. Ratio ofGlycopyrronium Bromide: Indacaterol:Fluticasone propionate As formulated1.0:2.0:2.5 HFA-134a—T = 0 1.0:1.9:3.1 HFA-134a—T = 1 month @1.0:1.9:2.9 40° C./75% RH) HFA-152a—T = 0 1.0:2.2:2.5 HFA-134a—T = 1month @ 1.0:2.2:2.3 40° C./75% RH)

It is clear from the data in Tables 4 and 5 above that the fine particledose and the fine particle fraction of the emitted dose aresignificantly higher when HFA-152a is used as the propellant as opposedto HFA-134a for all three drugs in the combination drug formulation.This represents an increase in the useful medication delivery dose. Thisimproved performance is also observed even after stress storage for 1month at 40° C. and 75% relative humidity.

In contrast to the HFA-134a formulations where all of the drugs achievea fine particle fraction of around 30%, the HFA-152a formulationsdeliver a fine particle fraction of 45% to 50%. Thus, HFA-152a providesa dramatically more effective and efficient delivery of all three drugswith the significant benefits of reducing the amount of medication usedto deliver an effective therapeutic dose, reducing the cost of treatmentand reducing the potential for systemic absorption of the drugs throughthe mouth and digestive tract resulting in adverse effects in thepatient.

Furthermore, whilst the MMAD of the HFA-134a based formulations rangefrom around 2.6 μm for glycopyrronium bromide to 4.8 μm for indacaterol,the particles delivered by HFA-152a have broadly equivalent sizes in therange of from 2.9 μm to 3.5 μm. This greater uniformity of particle sizeacross the three drugs is extremely important in ensuring that all threedrugs are delivered in the correct ratios to target lung tissue.Disparities in particle size can lead to non-uniform delivery withdifferential drug deposition and with consequential reduced therapeuticsynergy between the drugs. Thus, the data indicates that HFA-152a actsto minimise the extent of particle aggregation both for a particulardrug and between the different drugs.

Example 2

The stabilities of glycopyrronium bromide, indacaterol and fluticasonepropionate in HFA-134a and HFA-152a were investigated at time zero (T=0)and after storage, valve down, for 1 month (T=1M) and 3 months (T=3M) at40° C. and 75% relative humidity (RH) and at 25° C. and 60% relativehumidity (RH) in uncoated aluminium cans.

The drug formulations were prepared as described in Example 1 above andanalysed using the HPLC technique described in Example 1 above.

The results of investigating the chemical stability of theglycopyrronium bromide, indacaterol and fluticasone propionate drugformulations in HFA-152a and HFA-134a in uncoated aluminium cans areshown, respectively, in Tables 7 to 12 below.

TABLE 7 Chemical stability of glycopyrronium bromide in HFA-134a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T =3M@ 40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % totalimpurities Initial time T = 0 98.5 0.19 T = 1M @ 25/60 98.2 0.28 T = 1M@40/75 97.8 0.39 T = 3M @ 25/60 94.8 1.15 T = 3M @40/75 93.8 1.38

TABLE 8 Chemical stability of glycopyrronium bromide in HFA-152a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T =3M@ 40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % totalimpurities Initial time T = 0 98.5 0.19 T = 1M @ 25/60 98.6 0.25 T = 1M@40/75 98.4 0.35 T = 3M @ 25/60 97.6 0.55 T = 3M @40/75 97.2 0.82

TABLE 9 Chemical stability of indacaterol in HFA-134a in uncoatedaluminium cans based on percentage assay and total impurities uponstorage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T = 3M@40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % total impuritiesInitial time T = 0 100.5 <LoQ T = 1M @ 25/60 99.9 <LoQ T = 1M @40/7598.6 0.22 T = 3M @ 25/60 98.2 0.27 T = 3M @40/75 97.9 0.38

TABLE 10 Chemical stability of indacaterol in HFA-152a in uncoatedaluminium cans based on percentage assay and total impurities uponstorage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T = 3M@40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % total impuritiesInitial time T = 0 99.9 <LoQ T = 1M @ 25/60 100.5 <LoQ T = 1M @40/7599.1 0.05 T = 3M @ 25/60 98.8 0.11 T = 3M @40/75 98.5 0.15

TABLE 11 Chemical stability of fluticasone propionate in HFA-134a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T =3M@ 40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % totalimpurities Initial time T = 0 98.5 <LoQ T = 1M @ 25/60 98.2 0.19 T = 1M@40/75 97.8 0.38 T = 3M @ 25/60 94.8 0.58 T = 3M @40/75 93.8 0.69

TABLE 12 Chemical stability of fluticasone propionate in HFA-152a inuncoated aluminium cans based on percentage assay and total impuritiesupon storage at T = 0, T = 1M @ 40° C./75% RH and 25° C./60% RH and T =3M@ 40° C./75% RH and 25° C./60% RH. Time % Assay (LC) % totalimpurities Initial time T = 0 98.5 <LoQ T = 1M @ 25/60 98.6 <LoQ T = 1M@40/75 98.4 0.18 T = 3M @ 25/60 97.6 <LoQ T = 3M @40/75 97.2 0.58

It can be seen from the data in Tables 7 to 12 above that glycopyrroniumbromide, indacaterol and fluticasone propionate all exhibit superiorchemical stability under accelerated test conditions when HFA-152a isused as the aerosolization propellant rather than HFA-134a.

The invention claimed is:
 1. A pharmaceutical composition comprising:(i) a drug component comprising at least one pharmaceutically acceptablesalt of glycopyrrolate, at least one corticosteroid selected frombudesonide and beclomethasone dipropionate, and optionally at least onelong acting beta-2-agonist (LABA) selected from formoterol and thepharmaceutically acceptable salts thereof; and (ii) a propellantcomponent comprising 1,1-difluoroethane (HFA-152a), wherein thecomposition contains less than 500 ppm of water and less than 1000 ppmof oxygen based on the total weight of the pharmaceutical composition.2. The pharmaceutical composition of claim 1, wherein the at least onepharmaceutically acceptable salt of glycopyrrolate is glycopyrroniumbromide.
 3. The pharmaceutical composition of claim 1, wherein the drugcomponent additionally comprises the at least one long actingbeta-2-agonist (LABA).
 4. The pharmaceutical composition of claim 1,wherein the at least one pharmaceutically acceptable salt ofglycopyrrolate, the at least one corticosteroid and the at least onelong acting beta-2-agonist (LABA) where present are in a micronizedform.
 5. A pharmaceutical composition comprising: (i) a drug componentcomprising at least one pharmaceutically acceptable salt ofglycopyrrolate, at least one corticosteroid selected from budesonide andbeclomethasone dipropionate, and optionally at least one long actingbeta-2-agonist (LABA) selected from formoterol and the pharmaceuticallyacceptable salts thereof, and (ii) a propellant component comprising1,1-difluoroethane (HFA-152a), wherein the propellant component containsfrom 0.5 to 10 ppm of unsaturated impurities.
 6. The pharmaceuticalcomposition of claim 1 further comprising a surfactant componentcomprising at least one surfactant compound.
 7. The pharmaceuticalcomposition of claim 1 further comprising a polar excipient.
 8. Thepharmaceutical composition of claim 7, wherein the polar excipient isethanol.
 9. The pharmaceutical composition of claim 1 which is free ofone or more of (i) polar excipients, (ii) acid stabilisers and (iii)perforated microstructures.
 10. The pharmaceutical composition of claim1 which after storage in uncoated aluminium containers at 25° C. and 60%relative humidity for 3 months will produce less than 1.0% by weight ofimpurities from the degradation of the at least one pharmaceuticallyacceptable salt of glycopyrrolate based on the total weight of the atleast one pharmaceutically acceptable salt of glycopyrrolate and theimpurities.
 11. The pharmaceutical composition of claim 1 which afterstorage in uncoated aluminium containers at 40° C. and 75% relativehumidity for 3 months will produce less than 1.0% by weight ofimpurities from the degradation of the at least one pharmaceuticallyacceptable salt of glycopyrrolate based on the total weight of the atleast one pharmaceutically acceptable salt of glycopyrrolate and theimpurities.
 12. The pharmaceutical composition of claim 1, wherein atleast 96.0% by weight of the at least one pharmaceutically acceptablesalt of glycopyrrolate that is contained originally in thepharmaceutical composition immediately following preparation will bepresent in the composition after storage in uncoated aluminiumcontainers at 25° C. and 60% relative humidity for 3 months and afterstorage in uncoated aluminium containers at 40° C. and 75% relativehumidity for 3 months.
 13. The pharmaceutical composition of claim 1which when delivered from a metered dose inhaler yields a fine particlefraction of the at least one pharmaceutically acceptable salt ofglycopyrrolate which is at least 40 weight % of the emitted dose of theat least one pharmaceutically acceptable salt of glycopyrrolate.
 14. Thepharmaceutical composition of claim 1 in the form of a suspension. 15.The pharmaceutical composition of claim 1 in the form of a solution. 16.A metered dose inhaler (MDI) fitted with a sealed and pressurizedaerosol container that contains a pharmaceutical composition as claimedin claim 1.